The American Migraine Study reports that 32 million Americans, 11.8% of the population; suffer with at least one migraine headache annually, and that 23 million people in the US suffer with “severe migraine” (Stewart W F JAMA 1992; 267:64–9, Lipton, RB Headache. 2001; 41:638–645). Women account for two-thirds to three-fourths of all migraine patients, as gender specific prevalence in the. US is 17.6% for females and 6% for males using the IHS (International Headache Society) criteria for migraine diagnosis (Lipton RB, Neurology 1993; 43(Suppl 3):6–10). Twenty-five percent of women with migraine experience four or more severe attacks per month, 35% experience one to three severe attacks per month, and 40% experience one or less than one severe attack per month. Similar frequency patterns of migraine were observed in men (Stewart W F, JAMA 1992; 267:64–9). The overall average number of migraine attacks per year for men is 34 and 37.4 for women. In addition, “chronic recurrent headache” affects approximately 45 million Americans, the underlying pathophysiology for this condition is not yet fully understood (Meuller, L Journal of the American Osteopathic Association, 2000 September;100(9 Suppl):S14–21). Many researchers believe that these clinically significant headaches are primarily migraine-like (migrainous).
Headaches are one of the most common complaints heard by primary care physicians, accounting for over 10 million office visits each year in the United States. Three studies suggest that migraine prevalence may be increasing in the US (MMWR: Morbidity and Mortality Weekly Report 1991; 40:331–8; Stang P E, Neurology 1992; 42:1657–62; Pryse-Phillips W, Can J Neurol Sci 1992; 19:333–9). In fact, it may be that only the number correctly diagnosed is increasing. A very recent study of 2,524 subjects with “sinus headache” found that a full 90% were actually suffering from migraines (Saper, J. Presentation to American Headache Society, June 2002). The true incidence of migraine cannot be precisely known, but is very high.
Migraine is a severe and disabling condition. More than 85% of women and more than 82% of men with severe headache had some headache related disability (Stewart W F, JAMA 1992; 267:64–9). Approximately 33% were severely disabled or needed bed rest during an attack. Many studies have examined various aspects of headache related disability. Migraine is not just an episodic disease; it is also a chronic disease with episodic exacerbations. Many migraineurs live in fear knowing that an attack will disrupt their ability to work, to take care of their families, and to meet social obligations. Thus, there is some disability between attacks as well as during attacks. Quality of life measurements have shown that migraineurs, compared to those with other chronic illnesses, have lower scores in physical functioning and role functioning, and also experience more body pain (Dahlof, C Cephalalgia 1993; 13:233–7).
Migraine can induce a host of serious physical conditions: strokes, aneurysms, permanent visual loss, severe dental problems, coma and even death. According to the New England Journal of Medicine, “migraine can sometimes lead to ischemic stroke and stroke can sometimes be aggravated by or associated with the development of migraine.” Twenty-seven percent of all strokes suffered by persons under the age of 45 are caused by migraine. Stroke is the third leading cause of death in this country. According to the Mayo Clinic, twenty-five percent of all incidents of cerebral infarction were associated with migraines. Migraine and epileptic seizure disorders are also related. The most intimate relationship between the two being migraine-triggered epilepsy. Migraine affects up to 15% of the epileptic population. In basic terms, migraine and epilepsy are both disorders characterized by short-term, fleeting alterations of neurologic function, usually with normal neurological examinations between attacks.
Finally, the economic burden of migraine indicates its severity, costing the US economy over $14 billion per year.
Economic Cost of Migraine in the US(Hu, X Archives of Internal Medicine 1999 159: 813–8)US$ millionCost ElementMenWomenTotalMedical  1931,0331,226Missed workdays1,2406,6627,902Lost productivity1,4204,0265,446Total14,574 
Almost all of those affected by migraine use some medicine for pain, and almost all users of prescription pain relievers are also heavy users of over-the-counter (“OTC” or non-prescription) products. U.S. consumers spend over $6 billion annually on headache pain relievers (OTC and prescription products combined). OTC products used by migraineurs, such as aspirin, acetaminophen, ibuprofen and other common analgesics, exhibit side effects associated with both chronic use and short-term overuse, which may include liver damage, kidney damage, ulcers and stomach upset. These side effects are frequently severe. Each year, use of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen, account for an estimated 7600 deaths and 76000 hospitalizations in the United States (Fries J F. Assessing and understanding patient risk. Scand J Rheumatol Suppl. 1992;92:21–4.). Frequent use of OTC analgesics has been recognized as a substantial contributor to the development of daily headaches (“chronic daily headache”). Rebound headaches are also an issue, especially with products incorporating caffeine or aspirin.
The prescription migraine market in the US for triptans alone (a class of medication frequently used to treat migraines; examples include Imitrex, Zomig, Maxalt, etc.) was approximately $3.2 billion in 2001 (55 million prescriptions). Side effects commonly observed in this class of drugs include chest pain, shortness of breath, palpitations, paresthesias (sensation of burning, warmth, heat, numbness, tightness or tingling), asthenia (unusual tiredness or muscle weakness), dizziness, dry mouth, fatigue, hot flashes, nausea, vomiting, and sleepiness. Less common side effects include joint pain, CNS effects (agitation, anxiety, confusion, depression, irritability), eye problems (blurred vision, dry eyes, irritated eyes), chills, constipation, diarrhea, heartburn, dysphagia (trouble swallowing), euphoria, flatulence, heat sensitivity, hypertension, increased sweating, increased thirst, insomnia, muscle stiffness, muscle pain or spasms, polyuria (increased urination), pruritis (generalized itching of the skin), tinnitus (ringing in ears), tremor, vertigo, and warm or cold sensations. The fact that 55 million prescriptions are written each year in the United States for a class of drugs which cause up to 43% of users to experience adverse effects with any given dose (Geraud, G. Headache 2002 April; 42 Suppl 2:93–9) indicates the desperation of migraine patients and the need for better treatments. Total migraine prescription sales probably exceeded $4 billion and the market is growing at 4% annually (Brown, K The Scientist, 11[11]:1, May 26, 1997).
Less than half of those with migraine (48%) have been appropriately diagnosed, and only 41% of those with known migraine use prescription drugs, 57% relying exclusively on OTC medications for treatment of their migraines (Lipton, R Headache Vol 41, pp638–645, August 2001). The above study also revealed that more than half of all Americans who suffer from migraine headaches are prepared to put up with the pain rather than seek treatment from a physician, and that 26% had stopped seeing their doctor about the condition because they felt the doctor could not help. All of this suggests a heavy reliance on, even a preference for, OTC medication for the treatment of migraine. While there are no hard numbers for OTC migraine medicine sales, total OTC analgesic sales in the United States were $3.49 billion, up +2.6% vs. year prior, for the 52-weeks ending Jul. 15, 2000. OTC headache specific remedy sales were $2.65 billion, up 1.8%, on unit volume of 560 million. The fact that 57% of consumers rely entirely on OTC medications to treat a very painful, recurrent and debilitating disease demonstrates the extent of consumer preference for OTC medicines whenever available. Present OTC medications are limited in both number and effectiveness.
U.S. Pat. No. 6,103,218 to Brucker, et al., issued Aug. 15, 2000 discloses a composition and delivery system for administration of dried leaf particles of feverfew in the form of aqueous nasal spray composition. This mode of administration is stated to provide therapeutic moisturization of nasal mucous membranes, relief of migraine headaches and antispasmodic effect, such as to relieve menstrual cramping or aid digestion.
U.S. Pat. No. 6,312,736 Kelly, et al., issued Nov. 6, 2001 discloses an herbal composition for relief of pain and other symptoms associated with migraines and other types of headaches comprising: from about 46% to about 64% by weight of white willow bark extract; from about 8% to about 18% by weight of Kava Kava root extract; and from about 25% to about 41% by weight of at least one of feverfew extract and ginger root extract. The herbal composition disclosed therein is stated to be applied sublingually for rapid relief of pain.
U.S. Pat. No. 4,758,433 Johnson, et al., issued Jul. 19, 1988 discloses a preparation for pharmaceutical use, especially in the treatment of migraine, arthritis and bronchial complaints that contains a sesquiterpene lactone and is recovered from the plant Tanacetum parthenium by extraction using a pharmaceutically acceptable oil and is also delivered via said pharmaceutically acceptable oil, the oil being selected from the group consisting of saturated and un-saturated long chain hydrocarbons and fatty acids, vegetable and animal oils and polyoxyethylated derivatives thereof and reconstituted glycerides and esters thereof, wherein said hydrocarbon chain comprises between 10 and 25 carbon atoms, especially coconut oil, soybean oil or fish oil.
In addition to prescription and OTC medications, those with migraine headaches have attempted to treat this malady using herbal medicine or homeopathic treatments. Herbal medicine is defined as the use of herbs for their therapeutic or medicinal value. In the United States, herbal products are generally marketed as dietary supplements. An herb manufacturer or distributor can make no specific claims to diagnose, treat, cure or prevent any disease without having first obtained FDA approval. Nonetheless, information of the use of herbs for treatment of various maladies is widely available, including authoritative sources such as the Physicians Desk Reference (PDR) for Herbal Medicines, published by Thompson Medical Economics. Homeopathy is a separate theory of medical treatment, based on principles formulated by Samuel Hahnemann in the late 1700's. The practice of homeopathy is based on the belief that disease symptoms can be cured by infinitesimally small doses of substances which, in larger amounts, produce similar symptoms in healthy people. The Federal Food, Drug, and Cosmetic Act (the Act) recognizes as official the drugs and standards in the Homeopathic Pharmacopoeia of the United States and its supplements (Sections 201 (g)(1) and 501 (b), respectively).
Both feverfew and ginger have a long history of use as homeopathic and herbal remedies. Ginger has not historically been used for headache, but has been used with some success for relief of nausea. The administration of 1,000 to 2,000 mg of ginger orally by tablet has been found to effectively reduce nausea in the case of motion sickness (Lien, H C Am J Physiol Gastrointest Liver Physiol 2003 March; 284(3):G481–9). Ginger was investigated recently for its effect on nausea in morning sickness (Keating, A Altern Ther Health Med 2002 Sep–Oct; 8(5):89–91). In this study women took 1,000 mg of ginger in divided doses, the researchers concluding that ginger “may be helpful” in treatment of morning sickness. According to the Physician's Desk Reference for Herbal Medicines, the daily recommended dose of ginger for a variety of gastrointestinal symptoms (primarily various forms of nausea) ranges from 500 mg to 4000 mg. (PDR for Herbal Medicines, Thompson Medical Economics, Second Edition, Ginger, 339–342, 2000.) One published report suggests that ginger may be beneficial in the treatment of headache as it “has been reported in Ayurvedic and Tibb systems of medicine to be useful in neurological disorders.” (Mustafa, T J Ethnopharmacol 1990 Jul;29(3):267–73). Despite this, there have been no known clinical investigations of low dose ginger, sublingual ginger or ginger in the treatment of migraines or headache in general.
Feverfew is another herb that is widely available and has been investigated in modem times. Historically, feverfew is known to have been used in the treatment of fevers, from whence it derives its name, and also in rheumatic conditions. Feverfew is used in homeopathic remedies, but homeopathy recognizes no role for feverfew in the treatment of headaches. An authoritative homeopathic text is “A Dictionary Of Practical Materia Medica” by John Henry Clarke, M.D., recognized as such by the United States Food and Drug Administration, (see the “Compliance Policy Guide: Conditions Under Which Homeopathic Drugs may be Marketed” http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg400—400.html). The Clarke text gives no indication for the use of feverfew in the treatment of headaches. This same text defines the appropriate preparation of feverfew as “a tincture of fresh leaves.” A tincture is a concentrated herbal extract prepared by soaking an herb in alcohol for an extended period of time. The result is an alcoholic extract referred to by homeopathic practitioners as the “mother tincture.” This “mother tincture” is then subject to numerous serial dilutions with the resulting homeopathic drug being extremely dilute. Classic homeopathic remedies do not rely on any effect from the substance first contained in the starting material (“mother tincture” in this case) and often statistically contain virtually no actual molecules of the original substance (feverfew). Instead, these remedies rely on the “imprint” or “energy” of the original substance to exert an effect. Consistent with the precepts of homeopathy, the remedy thus prepared is felt to become increasingly potent, indeed stronger and more effective, as it becomes more and more dilute. Some of these homeopathic remedies may have been administered sublingually, or may yet be administered sublingually by those presently adherent to the practice. Such purported remedies would certainly contain less than 0.01 mg/ml of parthenolide and would not be employed for headache. It would be surprising to a practitioner in the art of homeopathy not only that feverfew is effective in the treatment of headache, but that the benefit not manifested at the extremely dilute concentrations employed by homeopathy is manifest by the present composition. There is little to no clinical support for any of the multitude of homeopathic remedies. Thus it is not surprising but still noteworthy that no clinical evidence exists for the effective use of feverfew in homeopathic medicine as a treatment for headache, especially as homeopathy does not recognize nor endorse this use.
Herbal medicine, as a field distinct from classical homeopathy, has in fact recognized the potential value of feverfew in the prophylactic (preventative) treatment of migraine. Fresh feverfew leaves have sometimes been chewed by subjects wishing to rid themselves of migraine. However, a common adverse effect reported by those who have used this technique is the generation sores in the mouth and sensitization of oral tissues. Additionally, many patients find this mode of administration to be crude and unpleasant. The concentration of feverfew administered by this method, even accounting for substantial dilution by the salivary juices, would remain far in excess of that employed in the present invention. The feverfew would in fact need to be diluted 1:100 by salivary juices to reach the maximum concentration employed in the present invention. In addition, the dosages historically and presently employed far exceed those of the present invention. In addition, the role of feverfew leaves in the treatment of migraine has always been restricted to prophylaxis (prevention), never having been applied to the acute treatment of headaches.
In addition to raw leaves, feverfew tablets or capsules have been and are employed by practitioners of herbal medicine. These are widely available in any “health food store” for purchase by the general public. The PDR for Herbal Medicines lists migraine, arthritis, rheumatic diseases and allergies as the indications for feverfew usage (PDR for Herbal Medicines, Thompson Medical Economics, Second Edition, Feverfew, 306–309, 2000.) Several studies published in leading medical journals, including “Lancet” (Murphy, J J Lancet 1988 Jul. 23;2(8604): 189–92), and “The British-Medical Journal” (Johnson, E S British Medical Journal 1985 Aug 31;291(6495):569–73), have suggested a potential role for feverfew in reducing the incidence and/or severity of migraines. The Murphy study administered one capsule of feverfew leaves to be swallowed by the patient, wherein each capsule contained about 2.19 micromoles of parthenolide (about 0.5 mg). The Johnson study administered two capsules of freeze dried feverfew powder every morning. The daily dose was therefore 50 mg feverfew. The parthenolide content of this feverfew powder was not reported. Patients reported a reduction in the number and/or severity of migraine attacks, with no side effects reported by either study. Most recently however, several systemic reviews of feverfew use in the prevention of migraine have been published (Vogler B K, “Feverfew as a preventive treatment for migraine: a systematic review.” Cephalalgia 1998 Dec; 18(10):704–8) and (Pittler M H, “Feverfew for preventing migraine.” Cochrane Database Syst Rev 2000;(3):CD002286) both of which reviews concluded that the efficacy of feverfew for the prevention of migraine “has not been established beyond reasonable doubt.” Pittler also noted that “the trial with the highest methodological quality, which was also among the largest, found no significant difference between feverfew and placebo.” Most clinicians in the United States do not consider feverfew an effective prophylactic treatment for migraine and as such do not endorse its use. Feverfew has not been used for the acute relief of migraine attacks. Each of the studies investigated only its prophylactic use. The use of feverfew acutely, for relief of headaches once they have begun, has not been studied and there is no scientific literature that directly suggests that it might be effective. In addition, the prophylactic effect is not said to be noticeable for some number of weeks (2–12) after having first initiated use of feverfew, regardless of the form of feverfew employed (tablets, leaves, etc.). Recommended dosages of feverfew tablets or capsules are 200 to 250 mg one to three times daily, there being no suggestion that alternate routes of administration or lesser doses might prove beneficial. Quite to the contrary, manufacturers generally emphasize the benefits of larger doses of feverfew. Again, neither the PDR For Herbal Medicines nor any other available herbal literature suggests the use of feverfew sublingually or as treatment of acute migraine attacks, it being believed that feverfew is wholly ineffective by such application for this purpose, or by any application for acute treatment.
A product currently available on the market is sold under the name MigraSpray®, which is stated to be a patented over the counter homeopathic drug intended to be a comprehensive approach for the treatment and prevention of migraine headaches. MigraSpray contains the active ingredients feverfew, polyporus, goldenseal and dandelion. MigraSpray is sprayed under the tongue (sublingual administration), which promotes enhanced bioavailability and rapid absorption by directly entering the bloodstream through the mucous membrane avoiding degradation from exposure to the gastrointestinal tract and liver. Product literature claims that this sublingual delivery system allows MigraSpray to provide rapid relief from migraine headache pain and other associated symptoms in an average of less than 7 minutes. However, this product, like other products sold as “homeopathic” treatments, delivers an extremely low dosage of feverfew. The amount of parthenolide reported to be present in this composition is 0.0112 mg/dose.
Additionally, it is noteworthy that the content of parthenolide in feverfew may vary to a great extent depending on the particular variety of Tanacetum parthenium plant grown, and also the manner of processing the feverfew herb. Parthenolide has been found to be unstable and sensitive to processing. Thus, the collection and processing steps carried out incorporating feverfew into a product may reduce or destroy the parthenolide content of the feverfew. Without a standardization of the parthenolide content of feverfew used in the process and careful control of the manufacturing process, great inconsistency is observed in parthenolide content from batch to batch of product.